Publications & Reports

NFkappaB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells.

de Valle E, Grigoriadis G, O'Reilly LA, Willis SN, Maxwell MJ, Corcoran LM, Tsantikos E, Cornish JK, Fairfax KA, Vasanthakumar A, Febbraio MA, Hibbs ML, Pellegrini M, Banerjee A, Hodgkin PD, Kallies A, Mackay F, Strasser A, Gerondakis S, Gugasyan R
Burnet Institute, Melbourne, VIC 3004, Australia Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.

Abstract

We examined the role of NFkappaB1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NFkappaB1 (Nfkappab1-/-) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity ofNfkappab1-/-Fo B cells that produce excessive levels of the proinflammatory cytokine interleukin 6 (IL-6). Despite enhanced germinal center (GC) B cell differentiation, the formation of GC structures was severely disrupted in theNfkappab1-/-mice. Bone marrow chimeric mice revealed that the Fo B cell-intrinsic loss of NFkappaB1 led to the spontaneous generation of GC B cells. This was primarily the result of an increase in IL-6 levels, which promotes the differentiation of Fo helper CD4+T cells and acts in an autocrine manner to reduce antigen receptor and toll-like receptor activation thresholds in a population of proliferating IgM+Nfkappab1-/-Fo B cells. We demonstrate that p50-NFkappaB1 repressesIl-6transcription in Fo B cells, with the loss of NFkappaB1 also resulting in the uncontrolled RELA-driven transcription ofIl-6.Collectively, our findings identify a previously unrecognized role for NFkappaB1 in preventing multiorgan autoimmunity through its negative regulation ofIl-6gene expression in Fo B cells.

Publication

  • Journal: The Journal of Experimental Medicine
  • Published: 28/03/2016
  • Volume: 213
  • Issue: 4
  • Pagination: 421-461

Author